Method for treating anxiety

ABSTRACT

The present invention relates a method for treating anxiety using azacyclic and azabicyclic oxadiazole compounds.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/006,584, filed Nov. 13, 1995.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/006,584, filed Nov. 13, 1995.

FIELD OF THE INVENTION

The present invention relates to a method for using azacyclic orazabicyclic compounds for treating anxiety in a human.

BACKGROUND OF THE INVENTION

Extensive research has been conducted for a number of years directedtoward the development of compounds capable of treating anxiety inhumans that are safer to the user and which exhibit fewer side-effects.For example, several clinically established anxiolytic agents such asthe barbituates, meprobamate and the benzodiazepines have numerous sideeffects such as potential for abuse and addiction or potentiation of theeffects of ethanol. The mechanism of action of these compounds isbelieved to involve the GABA/benzodiazepine receptor complex in humans.

Buspirone is another compound which has been studied for the treatmentof anxiety. The literature states that Buspirone interacts withreasonable potency only at the 5-HT_(1A) and dopamine receptors. AlfredGoodman, et al., Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 8:482 (1990); Tompkins et al. Research Communications inPsychology, Psychiatry, and Behavior, 5:4, p. 338 (1980).

The art has reported that compounds which act as agonists of thecholinergic muscarinic receptor can actually produce anxiety. See, Rischet al. Psychopharmacol. Bull., 19: 696-698 (1983), Nurnberger et al.Psychiatry Res., 9:191-200 (1983), and Nurnberger et al.Psychopharmacol. Bull., 17:80-82 (1982).

Surprisingly, we have discovered that a group of compounds havingmuscarinic cholinergic activity can be useful for treating anxiety. Thepresent invention relates to a method of treating anxiety. Morespecifically, the invention provides a method of treating anxiety inhumans using a specified tetrahydropyridine or azabicyclic oxadiazole orthiadiazole compound. The activity of these compounds is believed to bebased on agonist action at the m-1 muscarinic cholinergic receptor.

SUMMARY OF THE INVENTION

The present invention provides a method for treating anxiety in humanscomprising administering to a human in need thereof, an antianxiety doseof a compound of ##STR1## wherein W is oxygen or sulphur;

R is hydrogen, amino, halogen, NHR⁶, NR⁶ R⁷, R⁴, --OR⁴, --SR⁴, --SOR⁴,--SO₂ R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀-cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl) wherein R⁴ is C₁₋₁₅-alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, each of which is optionallysubstituted with one or more halogen(s), --CF₃, --CN, Y, phenyl orphenoxy wherein phenyl or phenoxy is optionally substituted withhalogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, --CF₃, --CONH₂ or--CSNH₂ ; or

R is phenyl or benzyloxycarbonyl, each of which is optionallysubstituted with halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃,--CF₃, --CONH₂ or --CSNH₂ ; or

R is --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y, --SR⁵ ZY, --Q--R⁵ --1Z--R⁴ or --S--R⁵--Z--R⁴ wherein Z is oxygen or sulphur, R⁵ is C₁₋₅ -alkyl, C₁₋₁₅-alkenyl, C₂₋₁₅ -alkynyl, and Y is a 5 or 6 membered heterocyclic group;and

G is selected from one of the following azacyclic or azabicyclic ringsystems: ##STR2## or G can optionally be substituted C₃ -C₈ cycloalkylor optionally substituted C₁₋₆ -alkyl wherein the substitution is --NR⁶R⁷ ;

R⁶ and R⁷ independently are hydrogen, C₁₋₆ -alkyl; or

R⁶ and R⁷ together with the nitrogen atom optionally form a 4- to6-member ring;

R¹ and R² independently are hydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅-alkynyl, C₁₋₁₀ -alkoxy, C₁₋₅ -alkyl substituted with --OH, --COR^(6'),CH₂ --OH, halogen, --NH₂, carboxy, or phenyl;

R³ is hydrogen, C₁₋₅ -alkyl, C₂₋₅ -alkenyl or C₂₋₅ -alkynyl;

R⁶ ' is hydrogen, C₁₋₆ -alkyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

is a single or double bond; or a pharmaceutically acceptable salt orsolvate thereof.

The invention claimed herein further provides a method for treatinganxiety wherein the anxiety is selected from the group consisting ofPanic Attack; Agoraphobia; Acute Stress Disorder; Specific Phobia; PanicDisorder; Psychoactive Substance Anxiety Disorder; Organic AnxietyDisorder; Obsessive-Compulsive Anxiety Disorder; Posttraumatic StressDisorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.

It is to be understood that the invention extends to each of thestereoisomeric forms of the compounds of the present invention as wellas the pure diastereomeric, pure enatiomeric, and racemic forms of thecompounds of Formula I.

DETAILED DESCRIPTION

As used herein the term "treating" includes prophylaxis of a physicaland/or mental condition or amelioration or elimination of the developedphysical and/or mental condition once it has been established oralleviation of the characteristic symptoms of such condition.

The term "antianxiety dose", as used herein, represents an amount ofcompound necessary to prevent or treat a human susceptible to orsuffering from anxiety following administration to such human. Theactive compounds are effective over a wide dosage range. For example,dosages per day will normally fall within the range of about 0.005 toabout 500 mg/kg of body weight. In the treatment of adult humans, therange of about 0.05 to about 100 mg/kg, in single or divided doses, ispreferred. However, it will be understood that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances including the condition to betreated, the choice of compound to be administered, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the chosen route of administration, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. While the present compounds are preferably administeredorally to humans susceptible to or suffering from anxiety, the compoundsmay also be administered by a variety of other routes such as thetransdermal, parenterally, subcutaneous, intranasal, intramuscular andintravenous routes. Such formulations may be designed to provide delayedor controlled release using formulation techniques which are known inthe art.

As used herein the term "anxiety" refers to an anxiety disorder.Examples of anxiety disorders which may preferredly be treated using aneffective amount of a named compound or pharmaceutically acceptable saltthereof include, but are not limited to: Panic Attack; Agoraphobia;Acute Stress Disorder; Specific Phobia; Panic Disorder; PsychoactiveSubstance Anxiety Disorder; Organic Anxiety Disorder;Obsessive-Compulsive Anxiety Disorder; Posttraumatic Stress Disorder;Generalized Anxiety Disorder; and Anxiety Disorder NOS.

Examples of anxiety disorders which may more preferredly be treatedusing an effective amount of a named compound or a pharmaceuticallyacceptable salt thereof include Panic Attack; Panic Disorder;Psychoactive Substance Anxiety Disorder; Organic Anxiety Disorder;Obsessive-Compulsive Anxiety Disorder; Posttraumatic Stress Disorder;Generalized Anxiety Disorder; and Anxiety Disorder NOS.

Examples of the anxiety disorders which are most preferredly treatedusing a named compound include Organic Anxiety Disorder;Obsessive-Compulsive Disorder; Posttraumatic Stress Disorder;Generalized Anxiety Disorder; and Anxiety Disorder NOS.

The named anxiety disorders have been characterized in the DSM-IV-R.Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed.(1994). The DSM-IV-R was prepared by the Task Force on Nomenclature andStatistics of the American Psychiatric Association, and provides cleardescriptions of diagnostic catagories. The skilled artisan willrecognize that there are alternative nomenclatures, nosologies, andclassification systems for pathologic psychological conditions and thatthese systems evolve with medical scientific progress.

The compounds employed in the invention are not believed to act via theGABA/benzodiazepine, 5HT1A, or D1 receptor systems in humans. Rather,the activity of the present compounds as antianxiety agents is believedto be based upon modulation of muscarinic cholinergic receptors.However, the mechanism by which the present compounds function is notnecessarily the mechanism stated supra., and the present invention isnot limited by any mode of operation.

As used herein with reference to the G substituent, the --(CH₂)_(r)--W-pyrazine moiety can be attached at any carbon atom of the azacyclicor azabicyclic ring. Further, R¹ and R² of the G substituent may bepresent at any position, including the point of attachment of the--(CH₂)_(r) --W-oxadiazole or --(CH₂)_(r) --W-pyrazine moiety.

Examples of pharmaceutically acceptable salts include inorganic andorganic acid addition salts such as hydrochloride, hydrobromide,sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate,tartrate, oxalate, or similar pharmaceutically-acceptable inorganic ororganic acid addition salts, and include the pharmaceutically acceptablesalts listed in Journal of Pharmaceutical Science, 66, 2 (1977) whichare known to the skilled artisan. The compounds of this invention mayform solvates with standard low molecular weight solvents using methodsknown to the skilled artisan.

As used herein with reference to the G substituent, the --(CH₂)_(r)--W-oxadiazole or --(CH₂)_(r) --W-pyrazine moiety can be attached at anycarbon atom of the azacyclic or azabicyclic ring. Further, R¹ and R² ofthe G substituent may be present at any position, including the point ofattachment of the --(CH₂)_(r) --W-oxadiazole or --(CH₂)_(r) --W-pyrazinemoiety.

Examples of pharmaceutically acceptable salts include inorganic andorganic acid addition salts such as hydrochloride, hydrobromide,sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate,tartrate, oxalate, or similar pharmaceutically-acceptable inorganic ororganic acid addition salts, and include the pharmaceutically acceptablesalts listed in Journal of Pharmaceutical Science, 66, 2 (1977) whichare known to the skilled artisan. The compounds of this invention mayform solvates with standard low molecular weight solvents using methodsknown to the skilled artisan.

As used herein with reference to the G substituent, the numbering shallbe as follows: ##STR3##

As used herein the term α shall refer to a position on the G substituentwhich is one position away from the N atom of the G substituent. Forexample, in the following illustration (1E), both positions 2 and 6 areconsidered α. The term γ shall refer to the position on the Gsubstituent which is opposite the N atom. For example, in theillustration (1E), position 4 is considered γ. Likewise, β shall referto the 3 and 5 position in the illustration. ##STR4##

As used herein with reference to the G substituent, the phrase "R⁶ andR⁷ together with the nitrogen atom optionally form a 4- to 6-memberring" means that R⁶ and R⁷ are each independently hydrogen,C₁ -C₆ alkyl;the R⁶ and R⁷ groups may optionally join to form a 4- to 6-member ringincluding the nitrogen. For example, optionally joined groups include,but not limited to: ##STR5##

As used herein the phrase "interacting with a muscarinic cholinergicreceptor" shall include compounds which block muscarinic cholinergicreceptors or modulate such receptors. Likewise, the term "interactingwith a nicotinic cholinergic receptor" shall include compounds whichblock or modulate the receptor. The phrase shall include the effectobserved when compounds act as agonists, partial agonists and/orantagonists at a cholinergic receptor.

As used herein, the term "alkoxide metal" means a metal suitable foralkoxide formation. Such alkoxide metals include, but are not limitedto, Li⁺, K⁺, Na⁺, Cs⁺, and Ca⁺⁺. Especially preferred alkoxide metalsinclude Li⁺, K⁺, and Na⁺.

As used herein, the term "halogen" means Cl, Br, F, and I. Especiallypreferred halogens include Cl, Br, and I.

The terms "C₁ -C_(n), alkyl" wherein n' can be from 2 through 15, asused herein, represent a branched or linear alkyl group having from oneto the specified number of carbon atoms. Typical C₁ -C₆ alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl,sec-butyl, tert-butyl, pentyl, hexyl and the like.

The terms "C₂ -C_(n), alkenyl" wherein n' can be from 3 through 10, asused herein, represents an olefinically unsaturated branched or lineargroup having from 2 to the specified number of carbon atoms and at leastone double bond. Examples of such groups include, but are not limitedto, 1-propenyl, 2-propenyl (--CH₂ --CH=CH₂), 1,3-butadienyl,(--CH═CHCH═CH₂), 1-butenyl (--CH═CHCH₂ CH₃), hexenyl, pentenyl, and thelike.

The term "C₂ -C₅ alkynyl" refers to an unsaturated branched or lineargroup having from 2 to 5 carbon atoms and at least one triple bond.Examples of such groups include, but are not limited to, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and the like.

The terms "halogen(C₁ -C₆)alkyl" and "halogen(C₂ -C₆)alkenyl" refer toalkyl or alkenyl substituents having one or more independently selectedhalogen atoms attached at one or more available carbon atoms. Theseterms include, but are not limited to, chloromethyl, 1-bromoethyl,2-bromoethyl, 1,1,1-trifluoroethyl, 1,1,2-trifluoroethyl,1,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl,trifluoroethylenyl, 3-bromopropyl, 3-bromo-1-propenyl, 2-bromopropyl,2-bromo-1-propenyl, 3-chlorobutyl, 3-chloro-2- butenyl,2,3-dichlorobutyl, 1-chloroethylenyl, 2-chloroethylenyl,5-fluoro-3-pentenyl, 3-chloro-2-bromo-5-hexenyl, 3-chloro-2-bromobutyl,trichloromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl,2,2-dichloroethyl, 1,4-dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl,1,1-dichloropropyl, and the like.

The term "C₂ -C₁₀ alkanoyl" represents a group of the formula C(O) (C₁-C₆) alkyl. Typical C₂ -C₁₀ alkanoyl groups include acetyl, propanoyl,butanoyl, and the like.

The term "(C₁ -C₆ alkyl) amino" refers to a monoalkylamino group.Examples of such groups are methylamino, ethylamino, iso-propylamino,n-propylamino, (n-propyl)amino, (iso-propyl)amino, n-propylamino,t-butylamino, and the like.

The term "C3-C_(n) cycloalkyl" wherein n=4-8, represents cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "substituted(C₅ -C_(n')) cycloalkyl" refers to a cycloalkylgroup as described supra wherein the cycloalkyl group may be substitutedwith from one to four substituents independently selected from the groupconsisting of hydrogen, C₁ -C₆ alkyl, NO₂, halogen, halogen(C₁-C₆)alkyl, halogen(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, CO₂ R²⁰, (C₁ -C₆alkyl) amino, --SR²⁰, and OR²⁰ ; wherein R²⁰ is selected from the groupconsisting of C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl, and C₂₋₁₅ -alkynyl.

The term "C₃ -C₈ cycloalkyl-(C₁₋₃)alkyl" represents an alkyl groupsubstituted at a terminal carbon with a C₃ -C₈ cycloalkyl group. Typicalcycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl,3-cyclopentylpropyl, and the like.

The term "C₅ -C₈ cycloalkenyl" represents an olefinically unsaturatedring having five to eight carbon atoms. Such groups include, but are notlimited to, cyclohexyl-1,3-dienyl, cyclohexenyl, cyclopentenyl,cycloheptenyl, cyclooctenyl, cyclohexyl-1,4-dienyl,cycloheptyl-1,4-dienyl, cyclooctyl-1,3,5-trienyl and the like.

The term "substituted (C₅ -C₈) cycloalkenyl" refers to a cycloalkenylgroup as described supra. wherein the cycloalkenyl group may besubstituted with from one to four substituents independently selectedfrom the group consisting of hydrogen, C₁ -C₆ alkyl, NO₂, halogen,halogen(C₁₋₆)alkyl, halogen(C₂ -C₆)alkenyl, C₂ -C₆ alkenyl, COR²⁰, C₂-C₁₀ alkanoyl, C₇ -C₁₆ arylalkyl, CO₂ R²⁰, (C₁ -C₆ alkyl) amino, --SR²⁰,and --OR²⁰ Wherein R²⁰ is selected from the group consisting of C₁₋₁₅-alkyl, C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl.

The term "C₅ -C₈ cycloalkenyl-(C₁ -C₃)alkyl" represents a C₁ -C₃ alkylgroup substituted at a terminal carbon with a C₅ -C₈ cycloalkenyl group.

As used herein, the phrase "5 or 6 membered heterocyclic group" means agroup containing from one to four N, O or S atom(s) or a combinationthereof, which heterocyclic group is optionally substituted at carbon ornitrogen atom(s) with C₁₋₆ -alkyl, --CF₃, phenyl, benzyl or thienyl, ora carbon atom in the heterocyclic group together with an oxygen atomform a carbonyl group, or which heterocyclic group is optionally fusedwith a phenyl group. The phrase "5 or 6 membered heterocyclic group"includes, but is not limited to, 5-membered heterocycles having onehetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycleshaving two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles,pyrazoles, imidazoles, thiazoles, purines); 5-membered heterocycleshaving three heteroatoms (e.g. triazoles, thiadiazoles); 5-memberedheterocycles having 3-heteroatoms; 6-membered heterocycles with oneheteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine,5,6-cycloheptenopyridine); 6-membered heterocycles with two heteroatoms(e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines,quinazolines); 6-membered heterocycles with three heteroatoms (e.g.1,3,5-triazine); and 6-member heterocycles with four heteroatoms.Particularly preferred are thiophenes, pyridines, and furans.

The term "heteroaryl" refers to a group which is a 5 or 6 memberedheterocycle containing one to four N, O, or S atoms or a combinationthereof.

As used herein the term "carboxy" refers to a substituent having thecommon meaning understood by the skilled artisan, wherein the point ofattachment may be through the carbon or oxygen atom of the group.

As used herein the term "aryl" means an organic radical derived from anaromatic hydrocarbon by the removal of one atom; e.g., phenyl ornaphthyl. Most preferably, aryl refers to C₆ -C₁₀ aryl, wherein the arylring system, including any alkyl substitutions, comprises from 6 to 10carbon atoms; e.g., phenyl, 3,3-dimethylphenyl, naphthyl, and the like.The aryl radical may be substituted by one or two C₁ -C₆ straight orbranched alkyl. The term "aryl(C₁ -C₃)alkyl" refers to any aryl groupwhich is attached to the parent moiety via the alkyl group.

As used herein the term "malfunctioning of the muscarinic cholinergicsystem" shall have the meaning accepted by the skilled artisan.Likewise, the term "malfunctioning of the nicotinic cholinergic system"shall have the art recognized meaning. For example the term shall referto, but is not in any way limited to, conditions such as glaucoma,psychosis, schizophrenia or schizophreniform conditions, depression,sleeping disorders, epilepsy, and gastrointestinal motility disorders.Other such conditions include Alzheimer's Disease and incontinence.

Compounds of this invention may be prepared by the process illustratedin Scheme II ##STR6##

The artisan will recognize that the starting materials for the processof Scheme II are commercially available or can be prepared using methodsfamiliar to the skilled artisan.

Compounds of Formula I wherein R is an R⁴ group, can be prepared usingmethods well known in the art. See for example, U.S. Pat. No. 5,043,345.

Further, compounds of Formula I may be prepared using the processillustrated in the following Scheme III ##STR7##

As used in Scheme III, Q may be N, O or S; R²⁴ is selected from thegroup consisting of hydrogen, R⁴, R⁵, R⁶, and R⁷ ; R²⁵ is selected fromthe group consisting of SOR⁴ and SO₂ R⁴ ; all other meanings are asdefined supra.

Additional compounds of Formula I may be prepared using the processillustrated by Scheme IV. ##STR8##

As used in Scheme IV, Hal, W, r, and G are as defined supra. As used inScheme IV, R²² and R²³ are independently selected from the groupconsisting of hydrogen, R⁶ and R⁷.

When the G substituent contains a secondary nitrogen protected by aprotecting group, the protecting group may be removed using standardmethods known to the skilled artisan. An especially preferred protectinggroup is carbamate. One particularly useful reference concerningprotecting groups is Greene, Protecting Groups in Organic Synthesis,(John Wiley & Sons, New York, 1981).

The pharmacological properties of the compounds of the invention can beillustrated by determining their capability to inhibit the specificbinding of ³ H-Oxotremorine-M (³ H-Oxo). Birdsdall N. J. M., Hulme E.C., and Burgen A. S. V. (1980). "The Character of Muscarinic Receptorsin Different Regions of the Rat Brain". Proc. Roy. Soc. London (SeriesB) 207,1.

³ H-Oxo labels muscarinic receptor in the CNS (with a preference foragonist domains of the receptors). Three different sites are labeled by³ H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively.Using the present experimental conditions only the high and mediumaffinity sites are determined.

The inhibitory effects of compounds on ³ H-oxo binding reflects theaffinity for muscarinic acetylcholine receptors.

All preparations are performed at 0°-4° C. unless otherwise indicated.Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenizedfor 5-10 s in 10 mL 20 nM Hepes pH: 7.4, with an Ultra-Turraxhomogenizer. The homogenizer is rinsed with 10 mL of buffer and thecombined suspension centrifuged for 15 min. at 40,000×g. The pellet iswashed three times with buffer. In each step the pellet is homogenizedas before in 2×10 mL of buffer and centrifuged for 10 min. at 40,000×g.

The final pellet is homogenized in 20 nM Hepes pH: 7.4 (100 mL per g oforiginal tissue) and used for binding assay. Aliquots of 0.5 mL is added25 μL of test solution and 25 μL of ³ H-Oxotremorine (1.0 nM, finalconcentration) mixed and incubated for 30 min. at 25° C. Non-specificbinding is determined in triplicate using arecoline (1 μg/mL, finalconcentration) as the test substance. After incubation samples are added5 mL of ice-cold buffer and poured directly onto Whatman GF/C glassfiber filters under suction and immediately washed 2 times with 5 mL ofice-cold buffer. The amount of radioactivity on the filters aredetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non specific binding.

Test substances are dissolved in 10 mL water (if necessary heated on asteam-bath for less than 5 min.) at a concentration of 2.2 mg/mL. 25-75%inhibition of specific binding must be obtained before calculation ofIC₅₀. The test value will be given as IC₅₀ (the concentration (nM) ofthe test substance which inhibits the specific binding of ³ H-oxo by50%). IC₅₀ =(applied test substance concentration) x(C_(x) /C_(o)-C_(x))nM where C_(o) is specific binding in control assays and C_(x) isthe specific binding in the test assay. (The calculations assume normalmass-action kinetics).

Furthermore the pharmacological properties of the compounds of theinvention can also be illustrated by determining their capability toinhibit ³ HPRZ (pirenzepine, N-methyl-³ H!) binding to rat cerebralcortex membranes.

Pirenzepine binds selectively to subtype of muscarinic receptors.Historically the type is named the M₁ -site, whereas pirenzepinesensitive site would be more appropriate. Although selective for M₁-sites pirenzepine also interact with M₂ -sites.

All preparations are performed at 0°-4° C. unless otherwise indicated.Fresh cortex (0.1-1 9) from male Wistar rats (150-200 g) is homogenizedfor 5-10 s in 10 mL 20 mM Hepes pH: 7.4, with an Ultra-Turraxhomogenizer. The homogenizer is rinsed with 2×10 mL of buffer and thecombined suspension centrifuged for 15 min. at 40,000×g. The pellet iswashed three times with buffer. In each step the pellet is homogenizedas before in 3×10 mL of buffer and centrifuged for 10 min. at 40,000×g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g oforiginal tissue) and used for binding assay. Aliquots of 0.5 mL is added20 μL of test solution and 25 μL of ³ HPRZ (1.0 nM, final conc.), mixedand incubated for 60 min. at 20° C. Non-specific binding is determinedin triplicate using atropine (1.0 μg/mL, final conc.) as the testsubstance. After incubation samples are added 5 mL of ice-cold bufferand poured directly onto Whatman GF/C glass fiber filters under suctionand immediately washed 2 times with 5 mL of ice-cold buffer. The amountof radioactivity on the filters are determined by conventional liquidscintillation counting. Specific binding is total binding minusnon-specific binding.

Test substances are dissolved in 10 mL water, at a concentration of 0.22mg/mL. 25-75% inhibition of specific binding must be obtained beforecalculation of IC₅₀.

The test value will be given as IC₅₀ (the concentration (nM) of the testsubstance which inhibits the specific binding of ³ HPRZ by 50%). IC₅₀=(applied test substance concentration) x(C_(x) /C_(o) -C_(x))nM whereC_(o) is specific binding in control assays and C_(x) is the specificbinding in the test assay. (The calculations assume normal mass-actionkinetics).

Test results obtained by testing some compounds of the present inventionwill appear from the following table 1.

                  TABLE 1                                                         ______________________________________                                                        .sup.3 H-Oxo-M                                                                         .sup.3 HPRZ                                          Compound        IC.sub.50, nM                                                                          IC.sub.50,nM                                         ______________________________________                                        1               81       56                                                   2               374      253                                                  3               19.3     14.5                                                 6               2.5      0.9                                                  4               25       21                                                   5               40       32                                                   7               16       6.7                                                  8               1040     >1000                                                9               36       30                                                   10              354      223                                                  11              56       53                                                   12              25       13                                                   13              74       42                                                   14              26       21                                                   15              14       13                                                   16              39       23                                                   17              17       4.5                                                  18              21       5.4                                                  19              121      108                                                  20              245      246                                                  21              26       123                                                  22              140      52                                                   ______________________________________                                                        Oxo-M    Pir                                                  Compound No.    IC-50, nM                                                                              IC-50, nM                                            ______________________________________                                        23              4.9      2.7                                                  24              2.2      0.54                                                 25              180      680                                                  26              >1000    >1000                                                27              >1000    >1000                                                28              >10,000  5710                                                 29              1.7      0.68                                                 30              4.4      0.82                                                 41              3.2      1.6                                                  42              9.1      4.8                                                  43              8.1      2.2                                                  31              3.4      1.7                                                  32              3.9      4.0                                                  33              1.5      0.7                                                  34              2.0      0.66                                                 35              3.2      0.54                                                 36              0.34     5.8                                                  37              1.3      0.76                                                 38              6.2      3.3                                                  39              10       80                                                   40              60       17                                                   ______________________________________                                    

The following Examples are studies to establish the usefulness of thenamed compounds for treating anxiety.

EXAMPLE 1 Punished Responding

The antianxiety activity of the compounds employed in the method of thepresent invention is established by demonstrating that the compoundsincrease punished responding. This procedure has been used to establishantianxiety activity in clinically established compounds.

According to this procedure, the responding of rats or pigeons ismaintained by a multiple schedule of food presentation. In one componentof the schedule, responding produces food pellet presentation only. In asecond component, responding produces both food pellet presentation andis also punished by presentation of a brief electric shock. Eachcomponent of the multiple schedule is approximately 4 minutes induration, and the shock duration is approximately 0.3 seconds. The shockintensity is adjusted for each individual animal so that the rate ofpunished responding is approximately 15 to 30% of the rate in theunpunished component of the multiple schedule. Sessions are conductedeach weekday and are approximately 60 min in duration. Vehicle or a doseof compound are administered 30 min to 6 hr before the start of the testsession by the subcutaneous or oral route. Compound effects for eachdose for each animal are calculated as a percent of the vehicle controldata for that animal. The data are expressed as the mean ± the standarderror of the mean.

EXAMPLE 2 Monkey Taming Model

Further, the antianxiety activity of the compounds is established bydemonstrating that the compounds are effective in the monkey tamingmodel. Plotnikoff Res. Comm. Chem. Path. & Pharmacol., 5: 128-134 (1973)described the response of rhesus monkeys to pole prodding as a method ofevaluating the antiaggressive activity of a test compound. In thismethod, the antiaggressive activity of a compound was considered to beindicative of its antianxiety activity. Hypoactivity and ataxia wereconsidered to be indicative of a sedative component of the compound. Thepresent study is designed to measure the pole prod response-inhibitioninduced by a compound of this invention in comparison with that of astandard antianxiety compound such as diazepam as a measure ofantiaggressive potential, and to obtain an indication of the duration ofaction of the compound.

Male and female rhesus, cynomologous or squirrel monkeys, selected fortheir aggressiveness toward a pole, are housed individually in a primatecolony room. Compounds or appropriate vehicle are administered orally orsubcutaneously and the animals are observed by a trained observer atvarying times after drug administration. A minimum of three days(usually a week or more) elapses between treatments. Treatments areassigned in random fashion except that no monkey receives the samecompound two times consecutively.

Aggressiveness and motor impairment are graded by response to a polebeing introduced into the cage as described in Table 1. The individualsresponsible for grading the responses are unaware of the dose levelsreceived by the monkeys.

                  TABLE 1                                                         ______________________________________                                        Grading of Monkey Response to Pole Introduction                               Response Grade      Description                                               ______________________________________                                        Attack   2          Monkey immediately grabbed and/or                                             bit pole as it was placed at opening                                          in cage.                                                           1          Monkey grabbed and/or bit pole only                                           after the tip was extended into the                                           cage 12 inches or more.                                            0          No grabbing or biting observed.                           Pole Push                                                                              2          Monkey grabbed the pole to attack it                                          or push it away.                                                   1          Monkey touched the pole only in                                               attempting to avoid it or rode on the                                         pole (avoidance).                                                  0          No pushing, grabbing or riding of                         Biting   2          Monkey bit aggressively and                                                   frequently.                                                        1          Monkey bit weakly or infrequently                                  0          No biting observed.                                       Ataxia   2          Monkey exhibited a marked loss of                                             coordination.                                                      1          Slight loss of coordination                                        0          No effects on coordination observed.                      Hypoactivity                                                                           2          Marked: Monkey was observed in a                                              prone position. May or may not have                                           responded by rising and moving away                                           when experimenter approached.                                      1          Slight: Monkey did not retreat as                                             readily when experimenter approached                               0          None.                                                     Antiaggression                                                                         +          Dose of drug was active in decreasing                     Activity of         global assessment of aggressive                           behavior                                                                      Drug Dose                                                                              -          Dose of drug was not active in                                                decreasing aggressive behavior                            ______________________________________                                    

EXAMPLE 3 Human Clinical Trials

Finally, the antianxiety activity of the named compounds can bedemonstrated by human clinical trials. The study was designed as adouble-blind, parallel, placebo-controlled multicenter trial. Thepatients are randomized into four groups, placebo and 25, 50, and 75 mgtid of test compound. The dosages are administered orally with food.Patients are observed at four visits to provide baseline measurements.Visits 5-33 served as the treatment phase for the study.

During the visits, patients and their caregivers are questioned andobserved for signs of agitation, mood swings, vocal outbursts,suspiciousness, and fearfulness. Each of these behaviors are indicativeof the effect of the test compound on an anxiety disorder.

For example, one study provided the following results:

    ______________________________________                                                 Placebo  25 mg    50 mg  75 mg                                       Behavioral                                                                             (N = 87) (N = 85) (N = 83)                                                                             (N = 87)                                    Event    n     (%)    n   (%)  n   (%)  n   (%)  p-Value                      ______________________________________                                        Agitation                                                                              40    (46)   34  (40) 24  (29) 20  (23) .006                         Mood swings                                                                            40    (46)   25  (29) 21  (25) 28  (32) .025                         Vocal    33    (38)   29  (34) 24  (29) 11  (13) .001                         Outbursts                                                                     Suspiciousness                                                                         32    (37)   23  (27) 26  (31)  7   (8) <.001                        Fearfulness                                                                            25    (29)   28  (33) 19  (23) 13  (15) .038                         ______________________________________                                    

Treatment groups are compared with respect to the number and percent ofpatients who ever had the symptom during the double-blind portion of thestudy (visits 5 through 33), at a severity that was worse than duringthe baseline visits (1 through 4).

Some examples of compounds contemplated for use in treating anxietyinclude, but are not limited to: (+/-)-3-butylthio-4-(azabicyclo2.2.2!octyl-3-oxy)-1,2,5-oxadiazole, (+/-)-3-(2-butyloxy)-4-(+/-)-3-azabicyclo 2.2.2!octyloxy)-1,2,5-oxadiazole, (+/-)-3-butyloxy-4-endo-(+/-)-6- 1-azabicyclo 3.2.l!octyloxy)!-1,2,5-oxadiazole,3-(2,2,3,3,4,4,4-heptaflurorobutyloxy)-4- (+/-)-3-(1-azabicyclo2.2.2!octyloxy)!-1,2,5-oxadiazole, 3-methoxy-4-(1-azabicyclo2.2.2!octyl-3-oxy)-1,2,5-oxadiazole, 3-pentylthio-4-(1-azabicyclo2.2.2!ocytl-3-oxy)-1,2,5-oxadiazole,trans-3-butyloxy-4-(2-dimethylaminocyclopentyloxy)-1,2,5-oxadiazole,3-butylthio-4-(3-azetidinyloxy)-1,2,5-oxadiazole,3-(3-N-(2-thiazolidonyl)propylthio)-4-(1-azabicyclo2.2.2!octyl-3-oxy)-1,2,5-oxadiazole, 3-chloro-4-(1-azabicyclo3.2.1!octyl-6-oxy)-1,2,5-oxadiazole,3-(2-2-thio-5-trifluoromethylthienyl)ethylthio)-4-azabicyclo2.2.2!octyl-3-oxy)-1,2,5-oxadiazole, 3-butylthio-4-3-±-endo-(1-azabicyclo 2.2.l!heptyloxy)!-1,2,5-oxadiazole, 3-hexyloxy-4-6-±-endo-(2-azabicyclo2.2.2!ocyloxy)!-1,2,5-oxadiazole,3-(4,4,4-trifluorobutylthio)-4-2-±-exo-(7-azabicyclo 2.2.1!heptyloxy)!-1,2,5-oxadiazole,3-(2-phenoxyethylthio)-4- 3-±-endo-(1-azabicyclo3.2.1!octyloxy)!-1,2,5-oxadiazole, 3-(5-hexenyloxy)-4-7-±-endo-(2-azabicyclo 2.2.1!heptyloxy)!-1,2,5-oxadiazole, 3-butyl-4-5-(1-azabicyclo 3.2.1!octyloxy)!-1,2,5-oxadiazole, and3-cyclobutylmethyl-4- 2-±-endo-(8-azabicyclo3.2.1!octyloxy)!-1,2,5-oxadiazole.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal, depot,subcutaneous, intravenous, intramuscular or intranasal, the oral routebeing preferred.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier, or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper, or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,gelatine, lactose, amylose, magnesium stearate, talc, silicic acid,fatty acid monoglycerides and diglycerides, pentaerythritol fatty acidesters, hydroxymethylcellulose and polyvinylpyrrolidone. Theformulations may also include wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents, or flavoring agents. Theformulations of the invention may be formulated so as to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed in unit form comprising fromabout 0.1 to about 100 mg in a pharmaceutically acceptable carrier perunit dosage.

Some prefered characteristics of compounds for the treatment of anxietyare:

A) W is S;

B) r is 1 or 2;

C) G is selected from het-1 and het-5;

D) G is unsaturated;

E) G is het-4;

F) G is an azabicycle having 7 ring carbon atoms and a nitrogen atom;

G) G is het-6;

H) r is 0;

I) R is selected from halogen, --OR⁵ Y, --SR⁵ Y, --OR⁵ ZY, --SR⁵ ZY,--OR⁵ ZR⁴, --SR⁵ ZR⁴, --OR⁴, and --SR⁴ ;

J) W is O;

K) m is 1;

L) n is 1;

M) p is 2;

N) G is het-3

O) G is het-2

P) a compound of Formula I

Q) a compound of Formula I'

R) a compound of Formula I

wherein W is oxygen or sulphur;

R is selected from the group consisting of hydrogen, amino, halogen,NHR⁶, NR⁶ R⁷, R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴, C₃₋₁₀ -cycloalkyl,C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂-(cycloalkylalkyl); R⁴ is selected from the group consisting of C₁₋₁₅-alkyl, C2-15-alkenyl, and C2-15-alkynyl, each of which is optionallysubstituted with one or more independently selected from the groupconsisting of halogen(s), --CF₃, --CN, Y, phenyl and phenoxy whereinphenyl or phenoxy is optionally substituted with one or more selectedfrom the group consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy,--OCF₃, --CF₃, --CONH₂ and --CSNH₂ ; or

R is phenyl or benzyloxycarbonyl, each of which is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, --CN, C₁₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃,--CF₃, --CONH₂ and --CSNH₂ ; or

R is selected from the group consisting of --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y,--SR⁵ ZY, --O--R⁵ --Z--R⁴ and --S--R⁵ --Z--R⁴ ;

Z is oxygen or sulphur;

R⁵ is selected from the group consisting of C₁₋₁₅ -alkyl, C₂₋₁₅-alkenyl, and C₂₋₁₅ -alkynyl;

Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic ringsystems: ##STR9## or G can optionally be substituted C₃₋₈ cycloalkylwherein the substitution is --NR⁶ R⁷ ;

R⁶ and R⁷ independently are selected from the group consisting ofhydrogen and C₁₋₆ -alkyl; or R⁶ and R⁷ together with the nitrogen atomoptionally form a 4- to 6-member ring;

R¹ and R² independently are selected from the group consisting ofhydrogen, C₁₋₁₅ -alkyl, C₂₋₅ -alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, andC₁₋₅ -alkyl substituted with a subsituent independently selected fromthe group consisting of --OH, --COR^(6'), CH₂ --OH, halogen, --NH₂,carboxy, and phenyl;

R³ is selected from the group consisting of hydrogen, C₁₋₅ -alkyl, C₂₋₅-alkenyl and C₂₋₅ -alkynyl;

R^(6') is selected from the group consisting of hydrogen and C₁₋₆-alkyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

p is 0, 1 or 2;

q is 1 or 2;

r is 0, 1 or 2;

is a single or double bond;

provided that when W is O and G is a saturated azabicyclic group havingfrom 7 to 11 ring carbon atoms and a nitrogen atom wherein the nitrogenatom is separated from the W atom by 2 to 3 ring carbon atoms;

or a pharmaceutically acceptable salt or solvate thereof;

S) The G substituent is selected from the group consisting of ##STR10##

U) R is selected from the group consisting of --SR^(4'), SOR^(4'), --SO₂R^(4'), substituted benzyloxycarbonyl wherein the substituents are oneor more independently selected from the group consisting of --CN,--OCF₃, --CF₃, --CONH₂ and --CSNH₂ ; or C₃₋₁₀ -cycloalkyl, C₄₋₁₂-(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂-(cycloalkylalkyl).

V) R is selected from the group consisting of R⁴, C₃₋₁₀ -cycloalkyl,C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂-(cycloalkylalkyl); and R⁴ is selected from the group consisting ofsubstituted C₅₋₁₅ -alkyl, optionally substituted C₂₋₁₅ -alkenyl, andoptionally substituted C₂₋₁₅ -alkynyl, wherein such substituent is oneor more independently selected from the group consisting of halogen(s),--CF₃, --CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₄ -alkoxy, --OCF₃,--CF₃, --CONH₂ and --CSNH₂.

W) G is selected from the group consisting of het-4, het-7, het-6wherein n=2; het-3 wherein one of n and m is 0 or 2; and het-3 whereinthe I or I' group is attached at the bridgehead of het-3.

Especially preferred compounds of this invention have thecharacteristics of A-F,P; A-F,Q; characteristics of A, G, H, M, F;characteristics of G-O,Q; or the characteristics of G-J,M,P; or G-J,M,Q.The characteristics of R and S may be particularly preferred.

Further, especially preferred R groups include phenyl,benzyloxycarbonyl, --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y, --SR⁵ ZY, --O--R⁴--Z--R⁵ or --S--R⁴ --Z--R⁵, --SOR⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂-(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂-(cycloalkylalkyl) wherein Z is oxygen or sulphur, R⁵ is C₁₋₁₅ -alkyl,C₂₋₁₅ -alkenyl, C₂₋₁₅ -alkynyl, Y is a 5 or 6 membered heterocyclicgroup containing one to four N, O or S atom(s) or a combination thereof,R₄ is C₁₋₁₅ -alkyl, C2-15-alkenyl, and C₂₋₁₅ -alkynyl.

Further, especially preferred G groups include the followingheterocycles: ##STR11## wherein the point of attachment to the--(CH₂)_(r) --W-- group is as indicated

Some particularly preferred G groups include ##STR12## It is anotherpreferred embodiment of this invention that G is not an azabicycle,particularly when W is oxygen.

Additionally, another embodiment of this invention which can bepreferred is that when W is O and C is alkyl, R is not halogen.

The invention will now be described in further detail with reference tothe following examples. The examples are provided for illustrativepurposes, and are not to be construed as limiting the scope of theinvention in any way.

EXAMPLE 1 (+/-)-3-Butyloxy-4-(1-azabicyclo 2.2.2!octyl-3-oxy)-1,2,5-oxadiazole

A suspension of 3,4-diphenylsulfonyl-1,2,5-oxadiazole oxide (4.6 g,0.126 mol, Ref. J.Chem. Soc. 1964, 904.) in 1-butanol (400 mL) washeated to 55°-60° C. as a solution of sodium 1-butyloxide (0.3 g Na, 40mL 1-butanol) was added dropwise. After 1 h, the solvent was evaporated,residue was treated with H₂ O, and the mixture extracted with ether(3X). The extracts were washed with H₂ O, dried, and the solventevaporated to give a white solid (3.15 g). The solid was heated toreflux overnight in P(OCH₃)₃ (30 mL) then poured into ice-H₂ Ocontaining HCl (6 mL, 5N). The mixture was extracted with ether, theextracts washed with brine, dried, and the solvent evaporated to give ayellow liquid. Radial chromatography (15% EtOAc/hexane) gave a clearliquid (1.85 g). The liquid was dissolved in THF (30 mL) and addeddropwise to a mixture prepared from 1-azabicyclo 2.2.2!octan-3-ol(1.85 g0.014 mol), THF (20 mL), and 1.6M n-butyl lithium in hexane (8.4 mL,0.013 mol). The reaction was then warmed to 52° C. for 5 h. The cooledreaction was acidified with dilute HCl and diluted wit ether. theaqueous fraction was washed with ether, made basic, and extracted withether. The extracts were dried and evaporated to give a clear liquid.The HCl salt (1.4 g) crystallized from CHCl₃ -EtOAc-ether, m.p.186°-188° C. (Compound 1).

We claim:
 1. A method for treating anxiety in a human comprisingadministering an antianxiety dosage of a compound of Formula I or thequaternized form thereof: ##STR13## wherein W is oxygen or sulphur;R ishydrogen, amino, halogen, NHR⁶, R⁴, --OR⁴, --SR⁴, --SOR⁴, --SO₂ R⁴,C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl,--Z--C₄₋₁₂ -(cycloalkylalkyl), --OR⁵ Y, --SR⁵ Y, OR⁵ --Z--Y, --SR⁵ ZY,--O--R⁵ --Z--R⁴, --S--R⁵ --Z--R⁴ ; or phenyl or benzyloxycarbonyl, eachof which is optionally substituted with one or more substituentsindependently selected from halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy,--OCF₃, --CF₃, --CONH₂ and --CSNH₂ ; R⁴ is C₁₋₁₅ -alkyl, C₂₋₁₅ -alkenyl,or C₂₋₁₅ -alkynyl, each of which is optionally substituted with one ormore independently selected halo, --CF₃, --CN, Y, phenyl or phenoxysubstituents, wherein the phenyl or phenoxy may also have halo, --CN,C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃, --CF₃, --CONH₂ or -CSNH₂substituents; Z is oxygen or sulphur; R⁵ is C₁₋₅ -alkylene, C₂₋₁₅-alkenylene, or C₂₋₁₅ -alkynylene; Y is a 5 or 6 membered heterocyclicgroup; and G is substituted C₃ -C₈ cycloalkyl or substituted C₁₋₆ -alkylwherein the substitution is --NR⁶ R⁷ ; or one of the following azacyclicor azabicyclic ring systems: ##STR14## R⁶ and R⁷ independently arehydrogen or C₁₋₆ -alkyl; or R⁶ and R⁷ together with the nitrogen atomoptionally form a 4- to 6-member ring; R¹ and R² independently arehydrogen, C₁₋₅ -alkyl, C2-5-alkenyl, C₂₋₅ -alkynyl, C₁₋₁₀ -alkoxy, orC₁₋₅ -alkyl substituted with a subsituent independently selected from--OH, --COR^(6') CH₂ --OH, halogen, --NH₂, carboxy, or phenyl; R³ ishydrogen, C₁₋₅ -alkyl, C₂₋₅ -alkenyl or C₂₋₅ -alkynyl; R^(6') ishydrogen or C₁₋₆ -alkyl; m, n, p and r independently are 0, 1 or 2; q is1 or 2; is a single or double bond; or a pharmaceutically acceptablesalt or solvate thereof.
 2. A method of claim 1 wherein W is S.
 3. Amethod of claim 1 wherein W is O; and G is an azacylic or azabicyclicring system.
 4. A method of claim 3 wherein G is an azabicyclic ring. 5.A method of claim 2 wherein r is 1 or
 2. 6. A method of claim 1 whereinG is selected from the group consisting of: ##STR15##
 7. A method ofclaim 6 wherein G is selected from the group consisting of ##STR16## 8.A method of claim 1 wherein the compound is(±)-3-Butyloxy-4-(1-azabicyclo 2.2.2!octyl-3-oxy)-1,2,5-oxadiazole or apharmaceutically acceptable salt or solvate thereof.
 9. A method ofclaim 1 wherein G is selected from the group consisting of het-4, het-7,het-6 wherein n=2; het-3 wherein one of n and m is 0 or
 2. 10. A methodof claim 9 whererin R is selected from the group consisting of C₃₋₁₀-cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and--Z--C₄₋₁₂ -(cycloalkylalkyl).
 11. A method of claim 1 wherein R isselected from the group consisting of R⁴, --OR⁴, SOR^(4'), --SO₂ R^(4'),C₃₋₁₀ -cycloalkyl, C₄₋₁₂ -(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and--Z--C₄₋₁₂ -(cycloalkylalkyl).
 12. A method of claim 1 wherein R isselected from the group consisting of R⁴, C₃₋₁₀ -cycloalkyl, C₄₋₁₂-(cycloalkylalkyl), --Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂-(cycloalkylalkyl); andR⁴ is selected from the group consisting ofsubstituted C₅₋₁₅ -alkyl, optionally substituted C₂₋₁₅ -alkenyl, andoptionally substituted C₂₋₁₅ -alkynyl, wherein such substituent is oneor more independently selected from the group consisting of halogen(s),--CF₃, --CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy isoptionally substituted with one or more substituents selected from thegroup consisting of halogen, --CN, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, --OCF₃,--CF₃, --CONH₂ and --CSNH₂.
 13. A method of claim 1 wherein R isselected from the group consisting of --SR^(4'), SOR^(4'), --SO₂ R^(4'),substituted benzyloxycarbonyl wherein the substituents are one or moreindependently selected from the group consisting of --CN, --OCF₃, --CF₃,--CONH₂ and --CSNH₂ ; or C₃₋₁₀ -cycloalkyl, C₄₋₁₂ - (cycloalkylalkyl) ,--Z--C₃₋₁₀ -cycloalkyl and --Z--C₄₋₁₂ -(cycloalkylalkyl).
 14. A methodof claim 1 wherein G is selected from the group consisting of ##STR17##15. A method of claim 1 wherein the anxiety is an anxiety disorder. 16.A method of claim 15 wherein the anxiety disorder is selected from thegroup consisting of Panic Attack; Agoraphobia; Acute Stress Disorder;Specific Phobia; Panic Disorder; Psychoactive Substance AnxietyDisorder; Organic Anxiety Disorder; Obsessive-Compulsive AnxietyDisorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder;and Anxiety Disorder NOS.
 17. A method of claim 16 wherein the anxietydisorder is selected from the group consisting of Panic Attack; PanicDisorder; Psychoactive Substance Anxiety Disorder; Organic AnxietyDisorder; Obsessive-Compulsive Anxiety Disorder; Posttraumatic StressDisorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.
 18. Amethod of claim 17 wherein the anxiety disorder is selected from OrganicAnxiety Disorder; Obsessive-Compulsive Disorder; Posttraumatic StressDisorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.